Breast cancer is the most common malignancy diagnosed among women worldwide, and is the leading cause of cancer mortality (Parkin et al., CA Cancer J. Clin. 55:74-108 (2005)). In 2005, more than 1.1 million women will be diagnosed with breast cancer and over than 400,000 women will die from this disease (Parkin et al., supra (2005)). Moreover, breast cancer disproportionately affects young women, as highlighted by the fact that it represents the leading cause of death from disease among women ages 25-54. Fortunately, while breast cancer incidence has steadily increased in Western countries over the past 50 years, breast cancer mortality rates have declined for more than a decade, due to continued advances in early detection, surgery, radiation, and adjuvant therapy. Indeed, nearly 90% of women diagnosed with breast cancer will survive for at least 5 years.
As a consequence of its high incidence and favorable prognosis, the prevalence of breast cancer is extremely high. More than 4 million women are currently living with a diagnosis of breast cancer, making this the most prevalent cancer in the world today (American Cancer Society, Breast Cancer Facts & Figures 2003, Atlanta, Ga., pp. 1-27 (2003); National Cancer Institute, Cancer Control and Population Sciences, U.S. National Institutes of Health, (2004); Parkin et al., supra (2005)). Among these women, tumor dormancy followed by recurrence—either local, regional, or distant—represents the most common cause of breast cancer mortality. Even among those patients whose breast cancers have not spread to axillary lymph nodes by the time of surgery, 25-year recurrence rates have been reported at 43-53% (Fisher et al., Lancet 364:858-868 (2004)). This suggests that, in many cases, tumor cells have already disseminated to distant sites by the time that breast cancers are diagnosed. Indeed, analysis of bone marrow specimens indicates that residual cancer cells are detectable in up to 40% of primary breast cancer patients who do not have any clinical or histopathological signs of metastasis (Pantel et al., Semin. Cancer Biol. 11:327-337 (2001); Solakoglu et al., Proc. Natl. Acad. Sci. U.S. A. 99(4):2246-51 (2002); Pantel et al., Clin. Cancer Res. 9(17):6326-34 (2003)). These residual neoplastic cells are capable of surviving multiple courses of chemotherapy, and persist in a latent state following the apparent cure of the tumor from which they arose (Thurm et al., Clin. Cancer Res. 9(7):2598-604 (2003)).
The peak hazard of recurrence for breast cancer in humans occurs in the interval between years 1 and 2 after surgery (Demicheli et al., Breast Cancer Res. 6:689-696 (2004); Retsky et al., Breast Cancer Res. Treat. 65:217-224 (2001); Saphner et al., J. Clin. Oncol. 14:2738-2746 (1996)). In fact, more than a quarter of all relapses in premenopausal, node-positive patients occur within the first 10 months following resection. Nevertheless, residual neoplastic cells may linger unrecognized for more than a decade before emerging as recurrent disease. Consequently, breast cancers that appear cured may resurface as local or distant tumor recurrences 10 or 20 years later (Fentiman et al., Breast 9:5-8 (2000); Fisher et al., supra (2004); Weiss et al., J. Clin. Oncol. 21:1825-1835 (2003)). These, and other observations, argue persuasively that breast cancer recurrence represents the single greatest obstacle to curing this disease.
Despite the central role that recurrence plays in breast cancer mortality, virtually nothing is known about the cellular or molecular events responsible for this ominous clinical event. To date, a limited number of clinical and molecular characteristics of breast cancers have been shown to correlate with relapse-free survival. In women with breast cancer, the most important factors for predicting recurrence are tumor size and the extent of lymph node involvement (Carter et al., Cancer 63:181-187 (1989); Valagussa et al., Cancer 41:1170-1178 (1978)). In addition to these clinical parameters, a number of molecular markers for aggressive tumor behavior can be used to identify breast cancer patients at high risk for recurrence, including HER2/neu expression, c-myc amplification, and estrogen receptor negativity (Coradini et al., Curr. Opin. Obstet. Gynecol. 16:49-55 (2004); Schlotter et al., Breast Cancer Res. 5:R30-36 (2003)). Expression of a recently-identified kinase, Hunk, has been identified as a biomarker of metastasis-free survival (U.S. patent application Ser. No. 10/032,256, filed Dec. 21, 2001 and U.S. provisional patent application No. 60/671,655, filed Apr. 15, 2005). However, none of these, or any other molecular prognostic markers, have been shown to play a causal role in breast cancer recurrence. As such, their mechanistic relationship to this process is purely speculative.
Given the large number of women currently living with a diagnosis of breast cancer, elucidating the molecular mechanisms that allow tumors to evade primary therapy and recur is a critical goal of breast cancer research. In particular, understanding the biology of tumor latency, as well as the events that lead to recurrence would permit improvements in the prediction, prevention, and treatment of breast cancer recurrence. Achieving this goal, however, has been hampered by the lack of animal models that faithfully recapitulate these fundamental steps of breast cancer progression. Such models are essential for the rational development and testing of therapeutics targeted against the residual population of neoplastic cells that is responsible for the majority of breast cancer deaths.
Further compounding difficulties in understanding breast cancer recurrence is the limited availability of clinical material for analysis. While molecular profiles for primary human breast cancers have become widely available, no comprehensive molecular analysis of recurrent human breast cancers currently exists. Consequently, not only is information lacking regarding pathways causally involved in recurrence, but also lacking is even a rudimentary understanding of the specific molecular features that distinguish recurrent breast cancers from the primary tumors from which they arose.
One molecular prognostic marker for poor clinical outcome in breast cancer patients is the proto-oncogene, HER2/neu. Amplification and overexpression of this receptor tyrosine kinase occurs in 15-30% of primary human breast cancers and is associated with aggressive tumor behavior, high rates of relapse, and poor prognosis (Berger et al., Cancer Res. 48:1238-1243 (1988); Slamon et al., Science 235:177-182 (1987)). In recent years, Trastuzumab (Herceptin®), a neutralizing antibody that inhibits the activity of HER2/neu, has been tested in clinical trials for patients with HER2/neu-amplified breast cancers. The efficacy of this agent in slowing disease progression and prolonging survival, even in advanced stages of disease, has been demonstrated in multiple studies (Baselga et al., J. Clin. Oncol. 14:737-744 (1996); Cobleigh et al., J Clin Oncol. 17:2639-2648 (1999); Slamon et al., N. Engl. J. Med. 344:783-792 (2001); Vogel et al., J. Clin. Oncol. 20:719-726 (2002); Wang et al., Semin. Oncol. 28:115-124 (2001); Wang et al., Semin. Oncol. 28:21-29 (2001)). However, even in cases in which Trastuzumab is combined with standard chemotherapeutic regimens, breast cancers often eventually become resistant to therapy and recur (Hortobagyi et al., Semin. Oncol. 28:43-47 (2001)). As with cancer recurrence in general, however, the mechanisms by which HER2/neu-amplified breast tumor cells evade the blockade of this pathway are poorly understood.
In light of these findings, it is clear that prior to the present invention, there was an unmet need in the art to study the cellular and molecular events involved in breast cancer recurrence, and to develop a method for assessing the risk of breast cancer recurrence based on a molecular prognostic marker that is independent of known prognostic markers and is likely to play a causal role in recurrence.